Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin

Kim, Madeline; Duca, Ester Del; Cheng, Julia; Carroll, Britta; Facheris, Paola; Estrada, Yeriel; Cha, Amy; Werth, John; Bissonnette, Robert; Nocka, Karl; Zang, Chuanbo; Pavel, Ana B.; Guttman‐Yassky, Emma

doi:10.1016/j.jaad.2023.02.064

Cited by 4 publications

(3 citation statements)

References 67 publications

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“…The maintenance of ISGA response with crisaborole may be explained by the findings of a recent phase 2a, single-center, intrapatient, vehicle-controlled, proteomic analysis of 40 adults with mild to moderate AD and 20 healthy participants [ 21 ]. In that study, crisaborole induced normalization of the AD proteome towards a non-lesional non-AD normal skin molecular phenotype, supporting the role of topical PDE4 inhibition in the treatment of mild to moderate AD.…”

Section: Discussionmentioning

confidence: 99%

“…In that study, crisaborole induced normalization of the AD proteome towards a non-lesional non-AD normal skin molecular phenotype, supporting the role of topical PDE4 inhibition in the treatment of mild to moderate AD. Crisaborole may be useful as a broad-spectrum agent in AD management given its potential to target several general and immune pathways (e.g., Th2, Th17/Th22, and Th1 activation associated with AD pathogenesis in various stages and in different phenotypes of AD) [ 21 – 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Maintenance of Investigator’s Static Global Assessment Response with Once-Daily Crisaborole in Participants with Mild to Moderate Atopic Dermatitis

Eichenfield,

Stein Gold,

Lynde

et al. 2024

Dermatol Ther (Heidelb)

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Introduction Treatments for atopic dermatitis (AD) often fail to achieve lasting disease control. In the CrisADe CONTROL phase III study (ClinicalTrials.gov: NCT04040192), participants aged ≥ 3 months with mild to moderate AD treated with once-daily (QD) crisaborole, following initial treatment success with crisaborole twice daily (BID), had longer periods of flare-free maintenance, a higher number of flare-free days, and a lower number of flares compared with those who received vehicle. The study was an exploratory analysis of data on the maintenance of response per Investigator’s Static Global Assessment (ISGA; ISGA score of 0 [clear] or 1 [almost clear]) during the CrisADe CONTROL study through week 52. Methods Exploratory endpoints were the time to ISGA response during the open-label run-in period, and the maintenance of ISGA response and the severity and duration of flares during the double-blind maintenance period. Outcomes were stratified by age (participants aged 3 months to < 12 years and ≥ 12 years) and duration of crisaborole BID treatment (< 4 weeks or ≥ 4 weeks) during the open-label run-in period. Results During the open-label run-in period, the median time to ISGA response was 41.5 days. From week 4 to week 52 of the double-blind maintenance period, the proportion of participants who maintained ISGA response was greater with crisaborole versus vehicle, and this difference was statistically significant up to week 36 ( P < 0.05). Duration of flare periods during the maintenance period were 54.1 and 54.0 days for the vehicle and crisaborole-treated groups, respectively. Numerically fewer crisaborole-treated participants experienced a flare with an ISGA score of ≥ 2 compared with vehicle-treated participants (64.8% vs. 74.4%, respectively). Findings were comparable across most subgroups. Conclusions Adult and pediatric participants with mild to moderate AD at baseline who had achieved responder criteria (treatment success) with crisaborole BID during the run-in period maintained response per ISGA with crisaborole QD during the double-blind maintenance period through week 52. Trial Registration ClinicalTrials.gov: NCT04040192.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Maintenance of Investigator’s Static Global Assessment Response with Once-Daily Crisaborole in Participants with Mild to Moderate Atopic Dermatitis

Eichenfield,

Stein Gold,

Lynde

et al. 2024

Dermatol Ther (Heidelb)

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“…Several studies have demonstrated that PDE4 inhibitors can reduce neutrophil infiltration in various tissues ( 29 , 30 ). Recent human proteomic analysis research revealed that the clinical improvement in AD with crisaborole correlated significantly with decreased levels of important protein biomarkers associated with neutrophils ( 31 ). In a previous study, we observed that crisaborole reduced the expression of CXCL1 and CXCL2 in a mouse model of AD ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis

Pavlenko,

Seven,

Bystrom

et al. 2023

Acta Derm Venereol

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Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, has been approved for the treatment of mild to moderate atopic dermatitis. Atopic dermatitis is often associated with increased pain. Using a mouse model, this study investigated whether crisaborole suppresses pain associated with atopic dermatitis and the potential mechanisms underlying it. The mouse model for atopic dermatitis was developed by repeatedly applying MC903. MC903-treated mice had increased spontaneous scratching (itch-related behaviour) and wiping behaviour (pain-related behaviour). Crisaborole was topically applied to the cheek skin of MC903-treated mice, and it reduced both itch- and pain-related behaviours in these mice. Immunofluorescence staining revealed that crisaborole reduced neutrophil infiltration and interaction of neutrophils with sensory neurones. Intradermal injection of S100A8/A9, proinflammatory neutrophil mediator, enhanced not only itch-related behaviours evoked by histamine or chloroquine, but also pain-related behaviours evoked by capsaicin. Calcium imaging of mouse dorsal root ganglion neurones revealed that pretreatment with S100A8/A9 significantly increased calcium responses to histamine and capsaicin, and the proportion of chloroquine-sensitive neurones. These findings suggest that the PDE4 inhibitor reduces itch and pain, in part by inhibiting infiltration of S100A8/A9-containing neutrophils in a mouse model of MC903-induced atopic dermatitis.

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Topical anti-inflammatory treatments for eczema: network meta-analysis

Lax,

Van Vogt,

Candy

et al. 2024

Cochrane Database of Systematic Reviews

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Background Eczema (atopic dermatitis) is the most burdensome skin condition worldwide and cannot currently be prevented or cured. Topical anti‐inflammatory treatments are used to control eczema symptoms, but there is uncertainty about the relative effectiveness and safety of different topical anti‐inflammatory treatments. Objectives To compare and rank the efficacy and safety of topical anti‐inflammatory treatments for people with eczema using a network meta‐analysis. Search methods We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries on 29 June 2023, and checked the reference lists of included studies. Selection criteria We included within‐participant or between‐participant randomised controlled trials (RCTs) in people of any age with eczema of any severity, but excluded trials in clinically infected eczema, seborrhoeic eczema, contact eczema, or hand eczema. We included topical anti‐inflammatory treatments used for at least one week, compared with another anti‐inflammatory treatment, no treatment, or vehicle/placebo. Vehicle is a 'carrier system' for an active pharmaceutical substance, which may also be used on its own as an emollient for dry skin. We excluded trials of topical antibiotics used alone, complementary therapies, emollients used alone, phototherapy, wet wraps, and systemic treatments. Data collection and analysis We used standard Cochrane methods. Primary outcomes were patient‐reported eczema symptoms, clinician‐reported eczema signs and investigator global assessment. Secondary outcomes were health‐related quality of life, long‐term control of eczema, withdrawal from treatment/study, and local adverse effects (application‐site reactions, pigmentation changes and skin thinning/atrophy were identified as important concerns through patient and public involvement). We used CINeMA to quantify our confidence in the evidence for each outcome. Main results We included 291 studies involving 45,846 participants with the full spectrum of eczema severity, mainly conducted in high‐income countries in secondary care settings. Most studies included adults, with only 31 studies limited to children aged < 12 years. Studies usually included male and female participants, multiple ethnic groups but predominantly white populations. Most studies were industry‐funded (68%) or did not report their funding sources/details. Treatment duration and trial participation were a median of 21 and 28 days (ranging from 7 days to 5 years), respectively. Interventions used were topical corticosteroids (TCS) (172), topical calcineurin inhibitors (TCI) (134), phosphodiesterase‐4 (PDE‐4) inhibitors (55), janus kinase (JAK) inhibitors (30), aryl hydrocarbon receptor activators (10), or other topical agents (21). Comparators included vehicle (170) or other anti‐inflammatory treatments. The risk of bias was high in 2...

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Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin

Cited by 4 publications

References 67 publications

Maintenance of Investigator’s Static Global Assessment Response with Once-Daily Crisaborole in Participants with Mild to Moderate Atopic Dermatitis

Maintenance of Investigator’s Static Global Assessment Response with Once-Daily Crisaborole in Participants with Mild to Moderate Atopic Dermatitis

Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis

Topical anti-inflammatory treatments for eczema: network meta-analysis

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